U.S. Pat. No. 4,526,988 teaches that 2'-deoxy-2',2'-difluoronucleosides are useful antiviral agents. European Patent Application 184,365 teaches the use of the same compounds as oncolytic agents. The synthetic process disclosed in the publications produces intermediates containing up to two centers of chirality. One such intermediate having a chiral center is a protected lactone consisting of erythro and threo enantiomers of the formulae ##STR1## wherein P is a protecting group. The publications teach the erythro enantiomer is preferred since it provides a carbohydrate which has the stereochemistry of naturally occurring ribose. A carbohydrate which has the stereo-chemistry of naturally occurring ribose is preferred since it provides final product nucleosides which exhibit superior biological activity. U.S. Pat. No. 4,526,988 teaches the preparation of the above described erythro enantiomer by first forming an alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxolan-4-yl)propionate, consisting of 3-R- and 3-S-hydroxy enantiomers, of the formulae ##STR2## wherein R.sup.4 and R.sup.5 are independently C.sub.1 -C.sub.3 alkyl, in a ratio of about 3 parts 3-R-enantiomer to about 1 part 3-S-enantiomer. The publication discloses that the 3-R-hydroxy enantiomer has the proper stereochemistry to provide the desired erythro enantiomer and that the 3-R- and 3-S-enantiomers can be separated by expensive, laborious column chromatography procedures.
The patent teaches that once the 3-R-hydroxy enantiomer is isolated it is next hydrolyzed under very mild conditions to form an unprotected lactone; namely, 2-deoxy-2,2-difluoro-D-erythro-pentofuranos-1-ulose, which has the formula ##STR3## The publication teaches that mild conditions useful for forming the above compound include the use of hydrolysis reagents such as mildly acidic ion exchange resins or relatively strong acids, such as aqueous acetic acid or chloroacetic acid. Both types of hydrolysis reagents can cause problems in the hydrolysis reaction. For example, the use of ion exchange resin requires such large quantities of water that, especially in larger scale reactions, the lactone often reverts back to its open chain precursor because of its sensitivity to water. The relatively strong acids, on the other hand, are less preferred hydrolysis reagents for converting the 3-R-hydroxy enantiomer to the unprotected lactone since they produce large amounts of undesirable reaction products, including unreacted starting material.
Finally, once the unprotected lactone has been formed it is converted to the protected erythro lactone described above by adding an hydroxy protecting group to the lactone's hydroxy groups.
A second chiral center is produced at the anomeric carbon atom when the keto portion of the lactone is converted to an alcohol. More specifically, the two anomers for the desired erythro configuration are identified as .alpha. and .beta. anomers of the formulae ##STR4## The unprotected hydroxy group at the 1-position is ultimately replaced by a heterocyclic base, such as cytosine, to provide protected precursors of the biologically active 2'-deoxy-2',2'-difluoronucleosides. The .beta. anomer precursor is preferred since it provides 2'-deoxy-2',2'-difluoronucleosides which possess superior biological activity.
U.S. Pat. No. 4,526,988 specifically illustrates the use of t-butyldimethylsilyl as a protecting group. When this protecting group is used in the synthesis of 2'-deoxy-2',2'-difluoronucleosides the product is composed of about a 4:1 .alpha./.beta. anomeric ratio. This product must be purified by expensive, laborious column chromatography procedures to isolate the desired .beta. anomer.
The present invention provides a convenient process for obtaining 2'-deoxy-2',2'-difluoronucleosides having the desired erythro and .beta. stereochemistry which eliminates the need for extensive column chromatography purification, as previously required. Accordingly, one object of the present invention is to provide a process for preparing a crystalline lactone which is stable, therefore minimizing reversion back to the open chain precursor, as well as minimizing the formation of undesirable reaction products. Another object of the present invention is to provide a process for selectively isolating the erythro lactone from an enantiomeric mixture of erythro and threo lactones. Yet another object of this invention is to provide a process for producing the erythro configuration of 2'-deoxy-2',2'-difluoronucleosides in about a 1:1 .alpha./.beta. anomeric ratio. A final object of the invention is to provide processes for selectively isolating .beta.-2'-deoxy-2',2'-difluorocytidine, or an organic or inorganic acid addition salt thereof, from about a 1:1 .alpha./.beta. anomeric mixture, such that approximately 99.0% pure .alpha. anomer is isolated.